HER3 belongs to the ErbB family of receptor tyrosine kinases, which includes four different receptors: ErbB-1 (EGFR, HER1), ErbB-2 (neu, HER2), ErbB-3 (HER3) and ErbB-4 (HER4) (Yarden et al, Nat. Rev. Mol. Cell. Biol, 2001, 2(2): 127-137). The receptor proteins of this family are composed of an extracellular ligand-binding domain, a hydrophobic transmembrane domain and a cytoplasmic tyrosine kinase-containing domain. Growth factors of the EGF family bind to most of the ErbB receptors and activate them. HER3 (ErbB3) is characterized by a lack of tyrosine kinase activity. EGFR, HER2 and recently HER3 have been associated with tumour formation. Recent studies, for example, have shown that EGFR is over expressed in a number of malignant human tissues when compared to their normal tissue counterparts. A high incidence of over expression, amplification, deletion and structural rearrangement of the gene coding for the EGFR has been found in biopsies of brain tumours. Amplification of the EGFR gene in glioblastoma multiforme tumours is one of the most consistent genetic alterations known. Elevated levels of HER3 mRNA have been detected in human mammary carcinomas. Recently, it has been shown that inhibition of Her2 and EGFR tyrosine kinase activity using tyrosine kinase inhibitors show limited effect on HER2-driven breast cancers due to a compensatory increase in HER3 expression and subsequent signalling through the PI3K/Akt pathway (Sergina et al., Nature, 2007, 445:437-441).
U.S. Pat. No. 6,277,640 to Bennett et al. discloses antisense compounds, compositions and methods for inhibiting the expression of HER3.
There is a need for agents capable of effectively inhibiting HER3 function.